Abstract
As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs) and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer.
Highlights
Pancreatic adenocarcinoma (PDAC) is notorious for its abysmal propensity of early lymphatic invasion, liver metastasis, recurrence, and poorest prognosis
Lymphatic metastasis is the concurrent effect of interaction among cancer cells, tumor microenvironment and pre(metastatic) site niche
From putative metastasis-initiating cells (MICs) formation to the subtle alteration of tumor microenvironment and pre/metastatic site niche, from escaping from primary mass to anchoring and adhesion at a new site of lymphatics, and a new tumor emerging in lymph node, every step could be deemed as a deliberate machination
Summary
Pancreatic adenocarcinoma (PDAC) is notorious for its abysmal propensity of early lymphatic invasion, liver metastasis, recurrence, and poorest prognosis. Multivariate analysis based on pancreatic cancer patients showed that lowlevel Smad and Smad expression had shown a significant negative correlation with lymph node metastasis [44, 45], while TGF-beta, playing a distinct role in PDAC pathogenesis, can mediate tumor promotion or a more aggressive phenotype attributing its effect on tumor cell and tumorsupportive microenvironment. CCR7 combined with its ligand CCL21 was recently reported to synergistically guide pancreatic cancer cells toward lymphatic vessels and promote lymph node metastasis [80, 81] Shields and his coworkers creatively verified in a 3-dimensional model that CCL19/CCL21-CCR7 axis mediated an autologous chemotaxis to the lymphatics via interstitial flow and gradient-dependence of autocrine CCL19/CCL21; and interestingly, further research revealed that interstitial flow-enhanced migration cannot be reduced by blockage of CCR7, which implicated that direct proteolysis may be the main cause of flow-enhanced migration in that it can be abolished by pan-MMP inhibitor GM6001[82]. Suppressing miR-141, and miR-200a/b/c, miR-429 Suppressing miR-34 family miR-20a miR-126
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